Process for the preparation of acylamino alkanol derivatives

ABSTRACT

A novel process for the production of 1-(acylamino-aryloxy)-3amino-propanol derivative having an excellent Beta -adrenergic blocking effect. The process comprises basically reacting a compound of the formula   WHEREIN Z is a hydrogen atom or a protective group bonded to the oxygen atom by an aliphatic ether linkage, and R stands for an alkyl or aralkyl group, with a compound of the formula   WHEREIN Ar stands for a substituted or unsubstituted benzene or naphthalene ring, Ac indicates an organic acid residue, and Y represents a hydrogen atom, a monovalent hydrocarbon radical having up to 12 carbon atoms or an organic acid residue, or Y may be bonded to the group Ac to form a diacyl group.

I United States Patent [191 Suzuki et al.

[451 Feb. 4, 1975 1 PROCESS FOR THE PREPARATION OF ACYLAMINO ALKANOL DERIVATIVES [75] Inventors: Yasushi Suzuki, Yokohama; Kunio Tsukamoto, Zushi, both of Japan [73] Assignee: TeikokuHormone Mfg. Co., Ltd.,

Minato-ku, Tokyo, Japan [22] Filed: May 1, 1972 [21] Appl. No.: 249,196

[52] US. Cl. 260/562 A, 260/390, 260/47 C, 260/551 S, 260/551 P, 260/556 AR, 260/558 P, 260/326 A, 260/326.44, 260/326 C [51] Int. Cl. C07c 103/38 8 Field of Search 260/562, 558,559, 556, 260/326, 471, 551

[56] References Cited UNITED STATES PATENTS 3,408,387 10/1968 Howe et a1 260/562 OTHER PUBLICATIONS Gaertner, Tetrahedron Letters, p. 343-347 (1967). Gaertner, J. Org. Chem, vol. 33, p. 523-530 (1968).

Primary ExaminerHarry l. Moatz Attorney, Agent, or Firm-Sherman & Shalloway [57] ABSTRACT A novel process for the production of l-(acylaminoaryloxy)-3-amino-propano1 derivative having an excellent B-adrenergic blocking effect. The process comprises basically reacting a compound of the formula wherein Z is a hydrogen atom or a protective group bonded to the oxygen atom by an aliphatic ether linkage, and R stands for an alkyl or aralkyl group, with a compound of the formula wherein Ar stands for a substituted or unsubstituted benzene or naphthalene ring, Ac indicates an organic acid residue, and Y represents a hydrogen atom, a monovalent hydrocarbon radical having up to 12 carbon atoms or an organic acid residue, or Y may be bonded to the group Ac to form a diacyl group.

11 Claims, N0 Drawings PROCESS FOR THE PREPARATION OF ACYLAMINO ALKANOL DERIVATIVES This invention relates to a process for the preparation of l-(acylamino'aryloxy-3amino propanol derivatives from tertiary azetidinol derivatives.

More specifically, this invention relates to a process for the preparation of l-(acylamino-aryloxy)-3-substituted-amino-propanol derivatives expressed by following general formula (Ill) oz Ac-1lv-Ar-o-cH -cH-cH -N (III) wherein Ar stands for a substituted or unsubstituted benzene or naphthalene ring, Ac indicates an organic acid residue, Y represents a hydrogen atom, a monovalent hydrocarbon radical having up to 12 carbon atoms or an organic acid residue, or Y may be bonded to the group Ac to form a diacyl group, Z is a hydrogen atom or a protective group bonded to the oxygen atom by an aliphatic ether linkage, and R stands for an alkyl or aralkyl group, or their non-toxic acid addition salts.

Compounds of above general formula (III) obtained by the process of this invention have a specific structure characterized in that an acylamino group is further bonded to the aryl group of the l-aryloxy-3-substituted-amino-propanol derivative.

It has heretofore been known that compounds of general formula (III) have the B-adrenergic blocking property. Especially, l-(4'-acetoamidophenoxy)-3-iso- H o-ca -'CH-CH -N H CH 2 CH (III-e) Nit-coca has a high organ selectivity, that is, this compound acts selectively on heart muscle alone, and therefore, the compound has been known as an excellent B-adrenergic blocking agent that can even be administered to patients suffering from cardiac insufficiency.

However, known processes for preparing l- (acylamino-aryloxy)-3-substituted-amino-propanol derivatives expressed by formula (Ill) or (Ill-e) inevitably include many complicated steps. Therefore, the reaction operations are troublesome and involve various difficulties in these known processes. Further, since incorporation of impurities formed by side reactions cannot be avoided with decrease of the yield of the end product, it costs a great deal to obtain the intended end product of high purity according to these known processes.

For instance, the conventional process for preparing l-(4-acetoamidophenoxy)-3-iso-propylamino-2- propanol of formula (Ill-e) requires many steps as expressed by the following reaction formula A (see propylamino-Z-propanol having the following structure 35 Chemical Abstracts, 65, 7099 (1966) )2 Egg}; ion Formula A H O-CH -Cg-9H on c H 0 Cl-CH C\l;I CH N02 2 6 5 CH(CH5)2 H c H OCH2-CH-CH2 O-CH -CH-CH --N 2 6 5 I l 2 2 CH l 2 e 5 CH 5 OH N CH I OH CH N02 NH2 ca c a ca O-CH2-CH-CH2-N CH O-OH -CH-CH NH0H I I H a; 2 5

OH CH5 OH NH-COCH5 arr-coon Another process expressed by the following reaction formula B has been known (Chemical Abstracts, 65, 7099 (1966) j:

Reaction Fggrtula B V 4 derivative is not at all attacked by the reaction but can be retained stably. Unexpected great advantages of the process of this invention are brought about by such In the process expressed by above reaction formula B, in order to react l-(4-acetamidophenoxy)-2,3- epoxypropane with an equimolar amount of iso-propyl amine, it is necessary to employ iso-propyl amine in great excess. Further, since the basicity of iso-propyl amine is higher than that of an aromatic amine, in the above process the acetyl group is split off by the ammonolysis reaction and as a result l-(4-aminophenoxy)- 2,3-epoxypropane or its iso-propylamino-substituted product is formed as a by-product, which further reacts with the epoxy ring. As a result, the yield of the intended product (lll-e) is reduced and incorporation of by-products into the intended product cannot be avoided. These are fatal defects of the known process expressed by reaction formula B.

- It has now been found that when according to the process of this invention a l-substituted-Ii-azetidinol or its protected derivative expressed by the following formula is reacted with an acylamino-phenol or acylaminonaphthol derivative expressed by the following formula Ac1l l-Ar-OH Y a l-(acylamino-aryloxy)-3-substituted-amino-propanol derivative expressed by the following general formula (lll) CH-CH -NHR can be obtained at a high purity and in a high yield by one step. In the above-mentioned process of this invention, if the resulting compound of formula (III) has a protective group as Z, the protective group is readily split off by a known method and the radical -OZ is readily converted to the hydroxyl group -OH. In the above general formulae (1), (ll) and (lll), each of Ac, Ar, Y, R and Z is as previously defined with respect to formula (Ill).

As is seen from the reaction between compounds expressed by above formulae (I) and (ll), the process of this invention is characterized in that the direct reaction of a phenol or naphthol derivative of formula (ll) having a substituted or unsubstituted acylamino group with a 3-azetidinol derivative of formula (I) containing a tertiary nitrogen atom results in ring-opening of the 3-azetidinol derivative of formula (I) and the intended l(acylamino-aryloxy)-3-substituted-amino-propanol derivative of formula (Hi) can be formed by one step while the acylamino group of the phenol or naphthol characteristic features.

This invention will now be illustrated in more detail.

TERTIARY AZETlDlNOL DERIVATIVE OF GENERAL FORMULA (I) In the tertiary azetidinol derivative of general formula (I), it is preferred that the group R is an alkyl group having up to 12 carbon atoms, especially up to 5 carbon atoms, or an aralkyl group having 7 to 9 carbon atoms. The alkyl group may be either a straightchain alkyl group or a branched-chain alkyl group, but a branched-chain alkyl group is preferred.

It is especially preferred that Z is a hydrogen atom (H) or a protective group (Za) and R is a branchedchain alkyl group of up to 5 carbon atoms as such, for example, iso-propyl, tert-butyl, iso-butyl and sec-butyl groups. The case where R is an iso-propyl group is especially advantages. When the Z standsfor a protective group, it may be any of the groups known to be protective groups for the hydroxyl group. Preferable examples of the protective group Za include those expressed by the following formula wherein R is any of the groups having such property as a whole can be split off under the reduction conditions; more specifically, R preferably stands for a hydrogen atom, an alkoxy group having up to 3 carbon atoms, such as methoxy, ethoxy and propoxy groups. an alkyl group having up to 3 carbon atoms, such as methyl, ethyl, n-propyl and iso-propyl groups. a halogen atom such as chlorine and bromine, a halogenated alkyl group such as a trifluoromethyl group, an amino group, a group convertible to an amino group such as a nitro group, or other electron-donor group, and n is an integer of from 1 to 3, preferably 1, it being especially preferred that the substituent (-R),, is bonded to the 4-position of the benzene ring, and alkoxyalkyl protective groups such as methoxymethyl, ethoxymethyl and benzyloxymethyl groups.

Among the tertiary azetidinol derivatives expressed by general formula (I), compounds expressed by the following formula (l-a) PROCESS FOR PREPARATION OF TERTIARY AZETIDINOL DERIVATIVE OF FORMULA (I) The lsubstituted-3azetidinols and hydroxyprotected derivatives thereof of general formula (I) to be used as starting substances in the process of this invention are novel compounds exclusive of a few exceptions. These compounds may be prepared, for instance, by a method comprising reacting a compound expressed by the following formula wherein X stands for a halogen atom or a reactive ester residue, and Za is as defined above with respect to the protective group Z, with a primary amine expressed by the following formula wherein R is as defined above, to form l-substitutedazetidinol derivative of the following formula, whose 3-position is protected,

and, if desired, splitting off the protective group Za from the so formed azetidinol derivative of formula (l-b) by a method known per se, for instance, by the hydrogen reduction, to thereby convert it to an azetidinol derivative expressed by the following formula HO i wherein R is as defined above.

For instance, l-iso-propyl azetidinol of the following formula ca N-CH CH which is the starting compound to be used for the preparation of the compound of formula (Ill-e), i.e., the most desired intended compound in the process of this invention, may readily be prepared by a method comprising reacting a compound expressed by the following formula CH Cl :H o-c 2 CH C1 with a compound expressed by the following formula CH NH -CH 5 and reducing the resulting compound of the following formula ea N-CH 5 on with hydrogen in the presence of a known reduction catalyst such, for example, as a Raney nickel catalyst.

Although the above reaction between the compound of formula (W) and the amine of formula (V) may be carried out in the absence of a solvent, in order to inhibit formation of diamines or polymers as by-products and obtain an azetidinol derivative of formula (l-b) in a high yield, it is preferable to conduct the reaction in the presence of a suitable inert liquid medium. Benzyl alcohol is most desirable as such inert liquid medium, but other organic solvents, for instance, high boiling point organic solvents such as xylene, mesitylene and decalin may also be used.

The primary amine of formula (V) may be added to the reaction system in the form of an aqueous solution. and it is possible to conduct the reaction while maintaining the state where the compound of above formula (IV) is dispersed in the aqueous solution ofthe primary amine of formula (V). In general, it is preferred that the primary amine is used in an amount exceeding the stoichiometric amount, for instance, in an amount of 25 moles per mole of the compound of formula (IV). Even if the primary amine is used in such molar excess, formation of diamines as by-products is hardly ob' served.

The reaction may be carried out at a temperature of l00C. or higher. ln order to shorten the reaction time, it is desired to conduct the reaction at 120-160C. In such case, the reaction is usually carried out for 10 to hours.

The hydrogen reduction ofthe compound of formula (l-b) may be accomplished at a temperature ranging from room temperature to l00C. under a hydrogen pressure of l to 100 atmospheres by employing a metal catalyst such, as for example, Raney nickel, Raney cobalt, Urushibara-nickel, palladium and platinum.

PHENOL OR NAPHTHOL DERIVATIVE OF FORMULA (ll) In this invention any optional member selected from acylaminophenols and acylaminonaphthols expressed by the following formula Ac-N-Ar-OH (II) Y wherein Ac, Ar and U are as defined above, is employed. In the compounds ofthe above general formula (ll), the groups and OH may be bonded to the phenylene group Ar in any of the ortho-, metaand para-positions, but it is preferred that they are bonded in the paraposition. When the group Aris a naphthylene group, the above two groups may be bonded to the naphthylene group in any of 1.2-, 1,3-, l,4, 1,5-, 1,6-, 1,7- and l,8-positions, but it is preferred that they are bonded in the 1,4-, 15- or 1,8-position.

As described hereinabove, the group Ac in general formula (ll) stands for an organic acid residue. As such organic acid residue acyl groups such as formyl, acetyl,

propionyLbenzoyl, ethoxycarbonyl, methoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and tert-butyloxycarbonyl groups; organic sulfonyl groups such as mesyl, benzylsulfonyl and tosyl groups; organic sulfinyl groups such as benzencsulfinyl and toluenesulfinyl groups; organic sulfenyl groups such as onitrophenylsulfenyl and p-nitrophenylsulfenyl groups; and organic phosphonyl groups such as benzenephosphonyl and rriethanephosphonyl groups may be exemplified. In addition, as an exception a triphenylmethyl group is used equivalently to the organic acid residues recited above. Therefore, this exceptional triphenylmethyl group is included in the organic acid residue in the instant specification and claims. Among these organic acid residues monoor di-carboxylic acid residues having 1 to 8 carbon atoms are preferable.

When group Y is a hydrocarbon group, preferable examples of group Y are alkyl groups having up to 3 carbon atoms, such as methyl and ethyl groups. The groups Ac and Y may be bonded to each other to form a diacyl group such as ethylenedicarbonyl, maleyl, phthalyl and naphthalyl groups. When Ac is a dicarboxylic acid residue, the groups Ac and Y in formula (11) are linked together and bonded to the nitrogen atom.

The phenylene or naphthylene group expressed as Arin formula (11) may have 1 to 3 substituents (R,, R or R3). These substituents R,, R and R may be the same or different and stand for an alkyl or alkenyl group of 1-4 carbon atoms, an alkoxy group of 1-4 carbon atoms, a hydroxyl group or an amino group. R, and R may be bonded to each other to form an alkylene or ketoalkylene group or to form a 5- or 6-membered heter'ocyclic ringthrough a hetero atom.

The group -Y in general formula (11) stands for a hydrogen atom, a monovalent hydrocarbon group having up to 12 carbon atoms or an organic acid residue, and further, the groups Ac and Y may be linked together to form a diacyl group such as exemplified above.

Among phenols and naphthols expressed by formula (11), those represented by the following formula (ll-a) wherein Ar stands for a phenyl or naphthyl group, especially preferably a phenyl group, are advantageous when respect to their pharmaceutical effects and accordingly, they are greatly preferred.

REACTION CONDITIONS In accordance with this invention, (acylaminoaryloxy)-3-substituted-amino-2-propanol derivatives (intended products) expressed by following formula (Ill) wherein Ac. Ar, Y. Z and R are as defined above. are formed by reacting a tertiary azetidinol derivative expressed by formula (1) with a phenol or naphthol expressed by formula (11), more specifically a phenol or naphthol substituted by a substituted or unsubstituted acylamino group in the presence or absence of an organic solvent which is inert to the reaction.

The reaction may be carried out in the absence of a solvent or in the presence of an inert solvent. preferably a non-polar organic solvent. as for example, benzene, xylene. ether, benzyl alcohol. decalin and dioxanc. In general, the reaction of this invention is allowed to advance at elevated temperatures ranging from to 250C, preferably to 180C, but the temperature range is not particularly critical in this invention. The reaction may be carried out under either atmospheric or elevated pressures.

The reaction of this invention is allowed to advance smoothly even in the absence of a catalyst. but if desired, it is possible to employ a basic catalyst such as solid potassium hydroxide. sodium hydroxide or triethylamine, or an acidic catalyst such as trifluoroacetic acid or a highly acidic cation-exchange resin.

In accordance with one preferable embodiment of this invention, a tertiary azetidinol derivative of formula (I) is reacted with a phenol or naphthol derivative expressed by formula (11) in the molten state or in the presence of an organic solvent inert to the reaction, such as benzyl alcohol and xylene, in the presence of a solid caustic alkali in an amount of 1/100 to 1/10 mole per mole of the phenol or naphthol. ln this embodiment it is advantageous to employ the phenol or naphthol in an amount slightly excessive based on the tertiary azetidinol derivative, for instance, in an amount of at least 1.1 moles, preferably at least about 1.2 moles, per mole of the tertiary azetidinol derivative.

Products expressed by general formula ([11) are formed by the above-mentioned reaction. Accordingly, in this invention, if, for instance, an azetidinol derivative expressed by formula (l-a) is reacted with a phenol or naphthol expressed by formula (ll-a) under reaction conditions such as explained above, a l-(acylaminoaryloxy-3-substituted-amino-2-propanol derivative expressed by the following formula wherein Ar, Z and R are as defined above, is formed. When Z in formula (lll-c) is a protective group (Za), the resulting compound is subjected to the known hydrogenation reaction, for instance, in the presence of a reduction catalyst such as mentioned above, to thereby split off the protective group (Za) and form a l-(acylamino-aryloxy)-3-substituted-amino-2- propanol derivative expressed by the following formula -NHR' (III-a) wherein Ar and R' are as defined above.

ln view of pharmaceutical effects, products in which Z in general formula (lll) stands for a hydrogen atom, namely products in which the protective group (2a) is split off, are preferred among products obtained according to the process of this invention.

Products expressed by formula (III) or (Ill-c), espceially products in which the protective group (Za) is split off (for instance, products expressed by formula (Ill-d) may be recovered in the form of free bases. It is also possible to convert the free bases to their acid addition salts. As such acid addition salts, salts of nontoxic inorganic or organic acids such. as for example. as hydrochlorides, hydrobromides, sulfates. succinates. tartarate and salicylates may be exemplified.

Non-toxic acid addition salts of compounds expressed by general formula (111) may also be formed directly by reacting an addition salt of a tertiary azetidino! derivative of formula (1) with a non-toxic acid such as mentioned above, with a phenol or naphthol expressed by general formula (II). Accordingly. non-toxic acid addition salts of 1-(acylamin0-aryloxy)-3- substituted-amino-2-propanol derivative expressed by above general formula (Ill-c) or (lIl-c) can be formed directly by the reaction between non-toxic acid addition salts of compounds of formula (l-a) and compounds of formula (ll-a).

1n the reaction for forming directly such non-toxic acid addition salts of compounds expressed by formula (11]), (ill-c) or (Ill-d), the same reaction conditions as explained hereinabove with respect to the synthesis of free bases may be adopted. When the above reaction is carried out in the presence of a solvent, it is preferable to employ organic solvents capable of dissolving at least partially acid addition salts of the compounds of formula (1) or (l-a). As such solvent polar solvents such. as for example, benzyl alcohol, phenetyl alcohol and dioxane may be advantageously used. It is preferred that such polar solvents have a basicity not higher than that of aniline, and use of nonbasic polar solvents is especially preferable and advantageous.

Typical compounds prepared by the process of this invention are exemplified for better illustrationfbut this invention is not at all limited to these compounds.

*1-tert-butylamino-3-(4-acetylamino-2 3 dimethylphenoxy)-2-propanol, 1-iso-propylamin0-3-( 4 -acetylamino-phenoxy)2- propanol,

*1-tert-butylamino-3-(40'-acetylamino-phenoxy)-2- propanol,

* 1-iso-propylamino-3-( 2 -acetylamino-phenoxy )-2- propanol,

* 1-tert-butylamino-3-( 2 '-acetylamino-phenoxy )-2- propanol,

*1-(4'-acetylamino-1-naphthyloxy)-3-(tertbutylamino)-2-propanol,

* l -iso-propylamino-3-(4'-acctylamino-phenoxy)-2- benzyloxypropane, and

*1-tert-butylamino-3-(4'-acetylamino-2',3'-

dimethylphenoxy)2-benzyloxypropane.

Products of formula (III) in which Z stands for a hydrogen atom, which are represented by the above recited compounds, have excellent ,B-adrenergic blocking property and are very effective for remedy and prevention of coronary troubles such as heart attack and arrhythmia.

Among products of formula (111) or (ll-c) prepared by the process of this invention, products having a protective group (Za) are novel compounds and are useful not only as intermediates for the synthesis of the products free ofthe protective group (Za), namely products in which Z stands for a hydrogen atom, but also as antiulcerative agents for the stomach and duodenum. because they have an activity for controlling secretion of gastric juice.

This invention will now be illustrated in more detail by reference to examples.

EXAMPLE 1 in a nitrogen current. 11.6 parts of p-acetamidophenol and 8.1 parts of 1-is0-propyl-3-azetidinol were dissolved in 50 parts of benzyl alcohol, and in this state 03 part of potassium hydroxide was added to the solution. The solution was heated at 140C. for 6 hours under agitation. After the mixture had been cooled. it was extracted with 2N hydrochloric acid. and the extract was made alkaline to obtain an oily substance. which was then extracted with chloroform. The extract was concentrated to dryness and the residue was recrystallized from n-butyl acetate to yield 13.3 parts of 1-(4'-acetamido-phenoxyl-3-iso-propylamino-2- propanol melting at l33-l 34C. The yield was 69 percent.

The hydrochloride of l-(4'-acetamindo-phenoxy)-3- iso-propylamino-Z-propanol had a melting point of 139-142C.

EXAMPLE 2 A mixture of 16.6 parts of p-acetamidophenol and 20.5 parts of 1(iso-propyl)-3benzyloxy-azetidine was heated in a nitrogen gas current at 170C. for 8 hours under agitation. The reaction mixture was then cooled and dissolved in parts of ether. The solution was washed with 50 parts of water and dried over anhydrous sodium sulfate. Ether was distilled off and the residue was subjected to distillation to yield 20.5 parts of 1-( p-acetamido-phenoxy)-2-benzyloxy-3-( isopropylaminolpropane boiling at 193-l96under 0.5 mm Hg.

EXAMPLE 3 To 3.6 parts of l-(p-acetamidophenoxy)-2- benzyloxy-3-( iso-propylamino-propane 10 parts of ethanol were added. Then, 4 parts of ethanol containing Raney nickel were added to the mixture in an autoclave, and the hydrogenation was conducted at 40C. for 5 hours while maintaining the hydrogen pressure in the autoclave at 40 kg/cm The reaction mixture was cooled and the catalyst was removed by filtration. When the filtrate was concentrated, 2.4 parts of l-(pacetamidophenoxy)-3-( iso-propylamino)-2-propanol having a melting point 132134C. were obtained.

EXAMPLE 4 A mixture of 16.6 parts of p-acetamidophenol and 1 1.5 parts of 1-(iso-propyl)-3-azetidinol in decalin was heated in a nitrogen. current at 150C. for 5 hours under agitation. The reaction mixture was cooled and dissolved in ether. The solution was washed with water and dried over anhydrous sodium sulfate. Ether was distilled off and the residue obtained was 18.9 parts of l-(p-acetamidophenoxy)-3-(iso-propylamino)-2- propanol having a melting point of l33135C.

EXAMPLE 5 In 50 parts of benzyl alcohol 19.7 parts of 4- acetamido-2,3-xylenol and 12.9 parts of l-tert-butyl-3- azetidinol, were dissolved and 0.5 part of potassium hydroxide was added to the solution while heating it to 100C. in a nitrogen current. The mixture was then heated at C. for 8 hours under agitation. The reaction mixture was cooled and 100 parts of 2N hydrochloric acid were added thereto. The resulting acidic aqueous solution was washed twice with 50 parts of ethyl acetate. The water layer was made alkaline by addition of 8 parts of 4N NaOH and extracted three times with 50 parts of ethyl acetate. The ethyl acetate layer was washed with 50 parts of water, dried over anhydrous sodium sulfate and then concentrated. When the concentrate was allowed to stand in the dark, crystals were precipitated. Recrystallization from ethyl acetate gave l2.4 parts of l-(4-acetamido-2',3'-xyloxy)-3- tert-butylamino-2-propanol having a melting point of l07-l08C. The yield was 52 percent.

4-Acetamido-2,3-xylenol was synthesized in the following manner.

In a nitrogen current, 5.3 parts of finely ground 4- amino-2,3-xylenol hydrochloride were well mixed with 3 parts of finely ground anhydrous sodium acetate. A mixture of 3 parts of anhydrous acetic acid and 6 parts of glacial acetic acid was added to the above mixture, and the resulting mixture was heated under reflux for 3 hours. The reaction mixture was cooled and the resulting solid was dissolved in 50 parts of hot water. When the solution was cooled, crystals were precipi- Qlggmical Structugg tated. Recrystallization from water gave 4.5 parts of 4- acetamido-2,3-xylenol having a melting point of l80-l8lC. The yield was 83 percent.

EXAMPLE 6 20.6 parts of 4-methanesulfonamidophenol, 1 L parts of l-iso-propyl-3-azetidinol and 0.5 part of potassium hydroxide were dissolved in 50 parts of benzyl alcohol, and the solution was heated at l30C. for hours under agitation. The reaction mixture was cooled and treated in the same manner as in Example 4. The resulting ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated, and when petroleum ether was added to the concentrate, crystals were formed. Recrystallization from ethyl acetate and petroleum ether gave 14.4 parts of H4- methanesulfonamido-phenoxy)-3-iso-propylamino-2- propanol melting at ll 27C. The yield was 48 percent.

EXAMPLE 7 The following compounds were synthesized by methods illustrated in the preceding examples.

Melting Point CH OCH2CH(OH)CH2NHCH 3 9s 101C. i 3

NHCOCH OCH CI-MoI-I'mH NHC(CH 5 123 125C. -l

I NHCOCH CH3 O OCI-I2CH(OH)C-I2NHCH 77 C.

If l q l NHCoCH oct-t ci-aomea uric(CH )3 o A 120 122 C. a

i NHCCCH (3H OCH CH(OH)CH NI-ICH 2 CH3 171 173C.

NHCO

H3 OCH CH CH CH NHCH 2 2 C 1 177 180C. l l

7 I T HCO Q- C12 21.9 Parts ofZ-benzyloxy-l ,3-dichloro-propane, 59.1 parts of iso-propylamine and 59.1 parts of water were taken into an autoclave, and the mixture was heated for Continued Chemical Structure CH3 ct-1 ca(oa)ca nacH l 1 0E m-1coc1-1=cnca i C113 OCH2CH(OH)CH2NHC1I V 1 naso on OCH ca 01-: CH 1\ 1 A2 2 H'CH \CN "3 U N CH3 SOZCHB EXAMPLE 8 48 hours under agitation. The reaction mixture was 3 cooled and treated in the same manner as in Example 1, followed by distillation under reduced pressure. As a result, 17.4 parts of 3-benzyloxy-l-(isopropylJ- azetidine boiling at ll07C. under 2 mm Hg were obtained. The yield was 85 percent.

EXAMPLE 9 azetidine boiling at 94-96C. under 2 mm Hg were obtained. The yield was 80 percent.

EXAMPLE 10 A solution of4.l parts of 3-benzyloxy-1-(iso-propy1)- azetidine in parts of ethanol was taken into an autoclave together with 2 parts of Raney nickel as a catalyst. and under a hydrogen gas pressure of 100 atmospheres, the mixture was agitated at C. for 15 hours to perform the reduction. The catalyst was removed by filtration and the remaining ethanol solution was concentrated to dryness. The resulting oily substance was subjected to distillation under reduced pressure, or dissolved in n-hexane and cooled. As a result 1.9 parts of 1-( iso-propyl-)3-azetidinol was obtained in the form of white crystals. The product had a melting point of 56-57C. and a boiling point of 76C. under 3 mm 65 Hg. The yield was 82 percent.

EXAMPLE 1 l A solution of4.4 parts of 3-benzyloxy-l-(tert-butyl)- azetidine in 30 parts of ethanol was taken into an autoclave together with 2 parts of Raney nickel as a cata- Melting Point lyst. Under a hydrogen gas pressure of 100 atmospheres, the mixture was stirred at 40C. for 15 hours to perform the reduction. The catalyst was separated by filtration, and the remaining ethanol solution was concentrated to dryness. The resulting oily substance was dissolved in n-hexane and cooled. As a result 2.0 parts of 1-(tert-butyl)-3-azetidinol melting at 4243C. were obtained. The yield was 76 percent.

EXAMPLE l2 1n nitrogen current, 1 1.6 parts of p-acetamidophenol and 16.0 parts of 1-iso-propyl-3-azetidinol hydrochloride were dissolved in 50 parts of benzyl alcohol, and the solution was heated at C. for 6 hours under agitation. After the reaction mixture had been evaporated, the residue was recrystallized from methanol-ethyl acetate to yield 14.2 parts of l-(4- acetamido-phenoxy)-3-iso-propylamino-2-propanol hydrochloride melting at l40-142C.

EXAMPLE 13 In nitrogen current, 19.7 parts of 4-acetamido-2,3- xylenol and 17.1 parts of l-tert-butyl acetidinol hydrochloride were added to 50 parts of benzyl alcohol, and the mixture was heated at 150C. for 6 hours under agitation. After the reaction mixture had been evaporated, the residue was recrystallized from methanol-ethyl acetate to yield 13 parts of l-(4'-acetamido-2,3-xyloxy)- 3-iso-propylamino-2-propanol hydrochloride melting at l29-131C.

EXAMPLE 14 In nitrogen current, 11.6 parts of p-acetamidophenol and 15.3 parts of l-iso-propyl-3-azetidinol h)- drochloride were mixed together, and the mixture was heated at C. for 5 hours. The resulting reaction mixture was recrystallized from methanol-ethyl acetate to yield 1 1.7 parts of l-(4-acetamido-phenoxy)-3-isopropylamino-2-propanol hydrochloride melting at l39l41C.

What we claim is:

1. A process for the preparation of a l-aryloxy-3- amino-propanol derivative of the formula wherein R represents a straight or branched chain alkyl group having up to 12 carbon atoms or an aralkyl group having 7 to 9 carbon atoms; Ar represents a benzene or naphthalene ring; R R and R represent. independently, a hydrogen atom, an a l k yl or alkenyl group having 1 to 4 carbon atoms, an alkoxy gr oup having 1 to 4 carbon atoms, a hydroxyl group or an amino group, or R. and R may be bonded together to form an alkylene or ketoalkylene group or to form a 5- or 6- membered heterocyclic ring with a hereto atom; Ac represents an organic acid residue selected from the group consisting of organic carboxylic acid residue, organic sulfonyl groups, organic sulfinyl groups, organic sulfenyl groups, organic phosphonyl groups and triphenylmethyl groups; Y represents hydrogen atom, an alkyl group having up to 3 carbon atoms or the group Ac, or Y may be bonded to the group Ac to form an ethylenedicarbonyl, maleyl, phthalyl or naphthalyl group; and Z is a hydrogen atom, an alkoxyalkyl group, a benzyloxymethyl group or a group of the formula l I (I) N- R wherein Z and R as as defined above, with a compound of the formula Ac N- Ar" 0H (II) (II) in the molten state.

6. The process of claim 1, wherein the reaction is carried out in the presence of an inert organic solvent.

7. The process of claim 6, wherein said inert organic solvent is selected from benzene, xylene, ether, benxyl alcohol, decalin or dioxane.

8. A process for the preparation of a l-aryloxy-3- amino-propanol derivative of the formula Ac -T-Ar"-O-CH -CH -CH -NHR (III -b) wherein R represents a straight or branched alkyl group having up to 12 carbon atoms or an aralkyl group having 7 to 9 carbon atoms; Ar" represents a benzene or naphthalene ring; R,, R and R represent, independcntly, a hydrogen atom, an alkyl or alkenyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxyl group or an amino group, or R, and R may be bonded together to form an alkylene or ketoalkylene group or to form a 5- -membered heterocyclic ring with a hetero atom; Ac represents an organic acid residue selected from the group consisting of organic carboxylic acid residues, organic sulfonyl groups, organic sulfinyl groups, organic sulfenyl groups, organic phosphonyl groups and a triphenylmethyl group; and Y represents a hydrogen atom, an alkyl group having up to 3 carbon atoms or the group Ac, or Y may be bonded to the group Ac to form an ethylenedicarbonyl, maleyl, phthalyl or naphthalyl group; which comprises reacting a compound of the formula wherein R is a hydrogen atom or an electron donor group selected from the group consisting of an alkoxy group having up to 3 carbon atoms, an alkyl group having up to 3 carbon atoms, a halogen atom, a halogenated alkyl group having up to 3 carbon atoms, amino group and nitro group; and n is an integer of l to 3; and

R is as defined above, with a compound of the formula T1 Ac N Ar" 0a wherein R,. R R3. Ar", Ac and Y are as defined above, to form a compound of the formula R OZ (III-d) wherein Ar represents a phenyl or naphthyl group and R represents a straight-chain or branched-chain alkyl group having 1 to 5 carbon atoms, which comprises reacting an azetidinol derivative expressed by the following formula wherein R is as defined above, with a compound ofthe formula CH CO-NH-ArOH wherein Ar is as defined above.

10. The process of claim 1, for the preparation of l- (acylamino-aryloxy)-3-amino-2-propanol derivative of the formula OH (III-d) wherein Ar represents a phenyl or naphthyl group and R represents a straight-chain or branched-chain alkyl group having 1 to 5 carbon atoms, which comprises reacting an azetidinol derivatives expressed by the following formula wherein R is as defined above, or a non-toxic acid addition 'salt thereof, with a compound of the formula CH CONH ArOH wherein Ar is as defined above, to form a compound of the formula ca C0-NH-Ar' -o-ca (ul'e) wherein Ar and R are as defined above, and thereaf- 5 ter catalytically hydrogenating the so formed compound at a temperature ranging from room temperature to C. under a hydrogen pressure of l to 100 atmospheres in the presence of a hydrogenating catalyst selected from Raney nickel, Raney cobalt, Urushibara-nickel, paradium and platinum.

11. The process of claim 1, wherein the reaction is carried out in the presence of a solid caustic alkali in an amount of l/lOO to l/l0 mole per mole of the compound of the formula (ll).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIGN Patent No 3,864,398 Dated February 4, 1975 Inventor(s) YASUSHI SUZUKI ET AL It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the Heading, insert the following: T

-- Claims priority, application Japan, May .7, 1971, 46/2986 3.

In column 16, line 27 thereof: cancel "5- 6-membered" and substitute 5- or 6-membered therefor.

Signed and sealed this 15th day of April 1975.

(32: 3.) Attest c. I'LARSHALL mm: RUTH C. 13 .202? Commissioner of Patents .-a.ttestin. Officer and Trademarks;

@7 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION patent No. 3 5 Dated February 4, 1975 Inventofls) Bernd Holthusen It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 6, line 31, delete "12'", second occurrence, and

insert 13' Column 6, line 33, delete "12", second occurrence, and

insert l3 Column 9, line 3 (claim 7) after "image" insert a Signed and sealed this 17th day of June 1975. 5

(SEAL) ACCQSC:

C. IIARSI-IAIL DANN RUTH C. 11. .5201? Commissioner of Patents Arresting Officer and Trademarks 

1. A PROCESS FOR THE PREPARATION OF A 1-ARYLOXY-3-AMINOPROPANOL DERIVATIVE OF THE FORMULA
 2. The process of claim 1, wherein the reaction is carried out at a temperature ranging from 130* to 250*C.
 3. The process of claim 1, wherein the reacTion is carried out in the absence of a catalyst.
 4. The process of claim 1, wherein the reaction is carried out in an inert gas atmosphere.
 5. The process of claim 1, wherein the compound of the formula (I) is reacted with a compound of formula (II) in the molten state.
 6. The process of claim 1, wherein the reaction is carried out in the presence of an inert organic solvent.
 7. The process of claim 6, wherein said inert organic solvent is selected from benzene, xylene, ether, benxyl alcohol, decalin or dioxane.
 8. A process for the preparation of a 1-aryloxy-3-amino-propanol derivative of the formula
 9. The process of claim 1, for the preparation of 1-(acylamino-aryloxy)-3-amino-2-propanol derivative of the formula
 10. The process of claim 1, for the preparation of 1-(acylamino-aryloxy)-3-amino-2-propanol derivative of the formula
 11. The process of claim 1, wherein the reaction is carried out in the presence of a solid caustic alkali in an amount of 1/100 to 1/10 mole per mole of the compound of the formula (II). 